Pharmacological evaluation of clinically relevant concentrations of (2R,6R)-hydroxynorketamine

Ende, Christopher W Am; Dutra, Jason K.; Tseng, Wei Chou; Weber, Mark L.; Bogart, Luke J; Hales, Katherine; Pang, Jincheng; Volfson, Dmitri; Ende, Christopher W. am; Green, Michael E.; Buhl, Derek L.

doi:10.1016/j.neuropharm.2019.04.019

Cited by 27 publications

(28 citation statements)

References 33 publications

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“…It has also been demonstrated that (2 R ,6 R )-HNK exerts antidepressant effects through AMPAR activation as AMPAR antagonist inhibited the antidepressant effects of (2 R ,6 R )-HNK 41 . By contrast, at a clinically relevant unbound brain concentration (0.01–10 μM), (2 R ,6 R )-HNK did not bind orthosterically or directly to functionally activated AMPARs 122 . Furthermore, (2 R ,6 R )-HNK failed to evoke AMPAR-centric changes in any electrophysiological endpoint from adult rodent hippocampal sections 122 .…”

Section: Opioid Systemmentioning

confidence: 78%

“…By contrast, at a clinically relevant unbound brain concentration (0.01–10 μM), (2 R ,6 R )-HNK did not bind orthosterically or directly to functionally activated AMPARs 122 . Furthermore, (2 R ,6 R )-HNK failed to evoke AMPAR-centric changes in any electrophysiological endpoint from adult rodent hippocampal sections 122 . Unfortunately, the AMPAR potentiator Org 26576 did not have antidepressant effects in depressed patients 123 .…”

Section: Opioid Systemmentioning

confidence: 78%

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Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites

et al. 2019

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Although the robust antidepressant effects of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine in patients with treatment-resistant depression are beyond doubt, the precise molecular and cellular mechanisms underlying its antidepressant effects remain unknown. NMDAR inhibition and the subsequent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation are suggested to play a role in the antidepressant effects of ketamine. Although (R)-ketamine is a less potent NMDAR antagonist than (S)-ketamine, (R)-ketamine has shown more marked and longer-lasting antidepressant-like effects than (S)-ketamine in several animal models of depression. Furthermore, non-ketamine NMDAR antagonists do not exhibit robust ketamine-like antidepressant effects in patients with depression. These findings suggest that mechanisms other than NMDAR inhibition play a key role in the antidepressant effects of ketamine. Duman’s group demonstrated that the activation of mammalian target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex is reportedly involved in the antidepressant effects of ketamine. However, we reported that mTORC1 serves a role in the antidepressant effects of (S)-ketamine, but not of (R)-ketamine, and that extracellular signal-regulated kinase possibly underlie the antidepressant effects of (R)-ketamine. Several lines of evidence have demonstrated that brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), are crucial in the antidepressant effects of ketamine and its two enantiomers, (R)-ketamine and (S)-ketamine, in rodents. In addition, (2R,6R)-hydroxynormetamine [a metabolite of (R)-ketamine] and (S)-norketamine [a metabolite of (S)-ketamine] have been shown to exhibit antidepressant-like effects on rodents through the BDNF–TrkB cascade. In this review, we discuss recent findings on the molecular and cellular mechanisms underlying the antidepressant effects of enantiomers of ketamine and its metabolites. It may be time to reconsider the hypothesis of NMDAR inhibition and the subsequent AMPAR activation in the antidepressant effects of ketamine.

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Section: Opioid Systemmentioning

confidence: 78%

Section: Opioid Systemmentioning

confidence: 78%

Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites

et al. 2019

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“…Additionally, (2R,6R)-HNK does not produce abuse-related effects up to concentrations 25 times greater than antidepressant doses, and it failed to substitute for (R,S)-ketamine in the drug discrimination or self-administration paradigms (Zanos et al, 2016). This reduction in abuse liability can be attributed to the inability of (2R,6R)-HNK to bind or inhibit NMDA receptors (Lumsden et al, 2019;Shaffer et al, 2019;Zanos et al, 2016).…”

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confidence: 99%

“…The present study (Zanos, Highland, Abbreviations: BDNF, brain-derived neurotrophic factor; CPP, conditioned place preference; CSDS, chronic social defeat stress; FST, forced swim test; HNK, hydroxynorketamine; LMA, locomotor activity; MDD, Major depressive disorder reported that (R)-ketamine displayed greater antidepressant potency than that of a deuterated version of (R)-ketamine, indicating that the (2R,6R)-HNK metabolite plays a role in the potency and possibly the sustained antidepressant-like effects of (R)-ketamine. Importantly, therapeutically relevant concentrations of (2R,6R)-HNK do not bind to or directly inhibit NMDA receptors or activate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (Lumsden et al, 2019;Shaffer et al, 2019). The antidepressant-like effects associated with the (2R,6R)-HNK are likely dependent upon synaptogenesis caused by increased AMPA receptor activity, brain-derived neurotrophic factor (BDNF) release, mGlu 2 receptor inhibition, and/or other downstream signaling pathways such as mechanistic target of rapamycin (mTOR).…”

mentioning

confidence: 99%

What role does the (2R,6R)‐hydronorketamine metabolite play in the antidepressant‐like and abuse‐related effects of (R)‐ketamine?

Hillhouse

Rice

Porter

2019

British J Pharmacology

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Major depressive disorder (MDD) is a major health concern in which approximately 30% of patients do not response to currently approved antidepressant medications and are classified as treatment-resistant patients. The noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine produces both rapid (<24 hr) and sustained (up to several weeks) antidepressant effects in treatmentresistant patients following acute or repeated i.v. infusions of ketamine (0.5 mg·kg −1 ), a finding that has been replicated across several clinical studies. Ketamine also has demonstrated abuse liability among illicit drug users and concerns regarding the possible neurotoxic, and psychotomimetic effects have limited ketamine's clinical use (see Hillhouse & Porter, 2015). These concerns have led to the development and evaluation of ketamine's isomers and their biologically active metabolites to assess safety concerns (i.e., reduced abuse concern), and to elucidate ketamine's mechanism of action.The recent paper by Zanos, Highland, Liu, et al. (2019) aims to fill these gaps in understanding ketamine's therapeutic potential by first examining if ketamine-associated abuse liability can be reduced. The (S)-ketamine enantiomer has higher affinity for NMDA receptors and is thought to be more responsible for the abuse-related effects of ketamine, in that preclinical data have found that (S)-ketamine produces antidepressant-like effects and abuse-related effects at comparable doses. For example, while (S)-ketamine produces antidepressantlike effects across several behavioral models at 10 mg·kg −1 ; (S)-ketamine also produces conditioned place preference (CPP), increases locomotor activity (LMA), and disrupts the startle reflex at 10 mg·kg −1 (Yang et al., 2015;Yang et al., 2017;Zanos et al., 2016;Zhang, Li, & Hashimoto, 2014). Conversely, (R)-ketamine appears to have reduced abuse liability as it failed to produce CPP, increased LMA, or disruption of the startle reflex response, although it should be noted that a limited dose range (10-20 mg·kg −1 ) was tested (Yang et al., 2015). Furthermore, results indicated that (R)-ketamine produces more potent and longer acting antidepressant-like effects, producing antidepressant-like effects as low as 5 mg·kg −1 (Zanos et al., 2016; Zanos, Highland, Liu, et al., 2019). The present study (Zanos, Highland, Liu, et al., 2019) builds upon these findings by demonstrating that (R)-ketamine produces abuse-related effects at doses four to 18 times higher than the antidepressant dose (5 mg·kg −1 ), including hyperactivity (40 mg·kg −1 ), CPP (40 mg·kg −1 ), motor impairments (20-40 mg·kg −1 ), and disrupted started reflex (90 mg·kg −1 ). In sum, the (R)-and (S)-ketamine enantiomers produce both antidepressantlike and abuse-related effects; however, the therapeutic window (i.e., antidepressant-like effects vs. abuse liability) is larger, and the antidepressant-like effects are sustained for longer periods of time for (R)ketamine, compared to (S)-ketamine. Taken together, with evidence which indic...

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“…While (18). On the other hand, (2R,6R)-HNK is hypothesized to act preferentially on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), although some evidence suggests that this action may be dose-specific and may not have a direct effect on depressive-like behavior (19,(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

et al. 2019

Preprint

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Number of words in the abstract: 227 (250 max)Number of words in the text: 3812 (4000 max) ABSTRACT BACKGROUND: Females are more likely than males to develop major depressive disorder (MDD) after exposure to stress. We previously reported that the administration of (R,S)-ketamine before stress can prevent stress-induced depressive-like behavior in male mice but have yet to assess efficacy in female mice or for other compounds, such as the metabolites of (R,S)-ketamine. METHODS:We administered (R,S)-ketamine or its metabolites (2R,6R)hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-HNK at various doses 1 week before one of a number of stressors, including contextual fear conditioning (CFC), learned helplessness (LH), and chronic immobilization stress (CIS), in male and female 129S6/SvEv mice. To examine the interaction between ovarian hormones and stress resilience, female mice also underwent ovariectomy surgery (OVX) and a hormone replacement protocol prior to drug administration. RESULTS: (R,S)-ketamine and (2S,6S)-HNK, but not (2R,6R)-HNK, attenuated learned fear in male mice. (R,S)-ketamine and (2R,6R)-HNK, but not (2S,6S)-HNK, significantly reduced stress-induced depressive-like behavior in male and female mice. (R,S)ketamine and (2R,6R)-HNK) were prophylactically effective at a lower dose (10 mg/kg and 0.025 mg/kg, respectively) in female mice than in male mice (30 mg/kg and 0.075 mg/kg, respectively). Moreover, ovarian-derived hormones were necessary and sufficient for prophylaxis in female mice. CONCLUSIONS:Our results suggest that prophylactics against stress-induced depressive-like behavior can be developed in a sex-specific manner and that ovarian hormones mediate prophylactic efficacy in females. To our knowledge, this is the first

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Pharmacological evaluation of clinically relevant concentrations of (2R,6R)-hydroxynorketamine

Cited by 27 publications

References 33 publications

Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites

Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites

What role does the (2R,6R)‐hydronorketamine metabolite play in the antidepressant‐like and abuse‐related effects of (R)‐ketamine?

Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

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